René Santer

University Medical Center Hamburg - Eppendorf, Hamburg, Hamburg, Germany

Are you René Santer?

Claim your profile

Publications (152)529.43 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different biallelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial β-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement.
    No preview · Article · Jan 2016 · The American Journal of Human Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.
    No preview · Article · Dec 2015 · The American Journal of Human Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Congenital disorders of glycosylation form a rapidly growing group of inherited metabolic diseases. As glycosylation affects proteins all over the organism, a mutation in a single gene leads to a multisystemic disorder. We describe a patient with TMEM165-CDG with facial dysmorphism, nephrotic syndrome, cardiac defects, enlarged cerebral ventricles, feeding problems, and neurological involvement. Having confirmed the diagnosis via prenatal diagnostics, we were able to observe the glycosylation right from birth, finding a pathological pattern already on the first day of life. Within the next few weeks, hypoglycosylation progressed to less sialylated and then also to hypogalactosylated isoforms. On the whole, there has not been much published evidence concerning postnatal glycosylation and its adaptational process. This is the first paper reporting changes in glycosylation patterns over the first postnatal weeks in TMEM165-CDG.
    No preview · Article · Aug 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital lactase deficiency is an extremely rare gastrointestinal disorder characterized by neonatal-onset watery diarrhoea and failure to thrive. We present the first genetically confirmed case of congenital lactase deficiency in Central Europe. After an uneventful pregnancy and birth, a male newborn of consanguineous parents of Turkish origin presented with watery diarrhoea. On day 17, he was admitted to hospital with weight loss, hypertonic dehydration, and metabolic acidosis. Additionally, the patient showed an elevated calcium concentration in blood and urine as well as nephrocalcinosis. Diarrhoea stopped during intravenous rehydration and when feeding a glucose-, galactose-, and lactose-free formula. Therefore, glucose-galactose-malabsorption was assumed. However, genetic testing of the SGLT1 (SLC5A1) gene was negative and, indeed, feeding maltodextrine did not result in recurrence of diarrhoea. In contrast, lactose feeding immediately caused watery diarrhoea, suggesting congenital lactase deficiency. Genetic testing of the LCT gene revealed homozygosity for a 1-bp deletion in exon 8 (c.3448delT). Because of the nature of the mutation, causing a frame shift and a premature termination of translation, congenital lactase deficiency was confirmed and intestinal biopsies were unnecessary. The patient's general condition improved substantially on a lactose-free diet, including hypercalcaemia, hypercalciuria, and nephrocalcinosis which, however, only disappeared after months. This case demonstrates (a) that congenital lactase deficiency should be considered in cases of severe neonatal diarrhoea, (b) that intestinal biopsies can be avoided in typical cases that are confirmed by genetic testing, and (c) that the associated nephrocalcinosis can be reversed on diet and an appropriate fluid management.
    Preview · Article · Jul 2015 · BMC Gastroenterology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Site-1 protease (S1P) cleaves membrane-bound lipogenic sterol regulatory element-binding proteins (SREBPs) and the α/β-subunit precursor protein of the GlcNAc-1-phosphotransferase forming mannose 6-phosphate (M6P) targeting markers on lysosomal enzymes. The translocation of SREBPs from the endoplasmic reticulum (ER) to the Golgi-resident S1P depends on the intracellular sterol content, but it is unknown whether the ER exit of the α/β-subunit precursor is regulated. Here, we have investigated the effect of cholesterol depletion (atorvastatin treatment) and elevation (LDL overload) on ER-Golgi transport, S1P-mediated cleavage of the α/β-subunit precursor, and the subsequent targeting of lysosomal enzymes along the biosynthetic and endocytic pathway to lysosomes. The data showed that the proteolytic cleavage of the α/β-subunit precursor into mature and enzymatically active subunits does not depend on the cholesterol content. In either treatment, lysosomal enzymes are normally decorated with M6P residues, allowing the proper sorting to lysosomes. In addition we found that in fibroblasts of mucolipidosis type II mice and Niemann-Pick type C patients characterized by aberrant cholesterol accumulation, the proteolytic cleavage of the α/β-subunit precursor was not impaired. We conclude that S1P substrate-dependent regulatory mechanisms for lipid synthesis and biogenesis of lysosomes are different. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Jun 2015 · The Journal of Lipid Research

  • No preview · Article · May 2015 · European Journal of Paediatric Neurology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ein 2,5 Jahre alter Junge wurde aufgrund zu¬nehmender Unruhe, Entwicklungsregression und Automutilation bei ausgeprägtem Juck¬reiz an Händen und Füßen vorgestellt. Um¬fangreiche Untersuchungen führten zur Dia¬gnose einer chronischen Quecksilberintoxika¬tion (Akrodynie, M. Feer). Unter Therapie mit dem Chelatbildner Dimercaptopropansulfon¬säure (DMPS) normalisierten sich die Queck¬silberkonzentrationen in Blut und Urin eben¬so wie der klinische Befund. Die Akrodynie ist eine seltene Erkrankung, die Kombination der Symptome aber spezifisch, sodass sie bei entsprechenden Beschwerden bedacht wer-den sollte.
    Full-text · Article · Apr 2015 · Monatsschrift Kinderheilkunde

  • No preview · Conference Paper · Mar 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings. Georg Thieme Verlag KG Stuttgart · New York.
    No preview · Article · Feb 2015 · Neuropediatrics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Enzyme replacement therapy (ERT) has been shown to improve outcome in classical infantile Pompe disease. The purpose of this study was to assess mortality, morbidity, and shortcomings of ERT in a larger cohort of patients treated outside clinical trials. To accomplish this, we retrospectively analyzed the data of all 23 subjects with classical infantile Pompe disease having started ERT in Germany between January 2003 and December 2010. Results: Ten patients (43%) deceased and four others (17%) became ventilator dependent. Seven infants (30.5%) made no motor progress at all, while seven (30.5%) achieved free sitting, and nine (39%) gained free walking. Besides all the seven patients (100%) attaining no improvement of motor functions, four out of the seven (57%) achieving to sit without support, and three out of the nine (33%) being able to walk independently, secondarily deteriorated, and died or became ventilator dependent. Sustained reduction of systolic function despite reversal of cardiac hypertrophy (n = 3), gastroesophageal reflux (n = 5), swallowing difficulties or failure to thrive (n = 11), recurrent pneumonias (n = 14), port system complications (n = 4), anesthesia-related incidents (n = 2), severe allergic reactions (n = 6), hearing loss (n = 3), and orthopedic deformities (n = 4) were problems frequently encountered. Conclusion: Although this study has important shortcomings due to its retrospective nature and because important variables potentially influencing outcome were not available for a substantial amount of patients, these data suggest that classical infantile Pompe disease still remains a life-threatening condition associated with high morbidity and often dismal prognosis. Currently, a relevant number of patients do not benefit definitely from ERT.
    Full-text · Article · Jan 2015

  • No preview · Article · Dec 2014 · Zeitschrift für Geburtshilfe und Neonatologie

  • No preview · Article · Dec 2014 · Zeitschrift für Geburtshilfe und Neonatologie

  • No preview · Article · Dec 2014 · Zeitschrift für Geburtshilfe und Neonatologie
  • [Show abstract] [Hide abstract]
    ABSTRACT: In humans, lack of phenylalanine hydroxylase (Pah) activity results in phenylketonuria (PKU), which is associated with the development of severe mental retardation after birth. The underlying mechanisms, however, are poorly understood. Mutations of the Pah gene in Pah(enu2/)c57bl6 mice result in elevated levels of phenylalanine in serum similar to those in humans suffering from PKU. In our study, long-term potentiation (LTP) and paired-pulse facilitation (PPF), measured at CA3-CA1 Schaffer collateral synapses, were impaired in acute hippocampal slices of Pah(enu2/)c57bl6 mice. In addition, we found reduced expression of presynaptic proteins, such as synaptophysin and the synaptosomal-associated protein 25 (SNAP 25), and enhanced expression of postsynaptic marker proteins, such as synaptopodin and spinophilin. Stereological counting of spine synapses at the ultrastructural level revealed higher synaptic density in the hippocampus, commencing at 3 weeks and persisting up to 12 weeks after birth. Consistent effects were seen in response to phenylalanine treatment in cultures of dissociated hippocampal neurons. Most importantly, in the hippocampus of Pah(enu2/)c57bl6 mice we found a significant reduction in microglia activity. Reorganization of hippocampal circuitry after birth, namely synaptic pruning, relies on elimination of weak synapses by activated microglia in response to neuronal activity. Hence, our data strongly suggest that reduced microglial activity in response to impaired synaptic transmission affects physiological postnatal remodelling of synapses in the hippocampus and may trigger the development of mental retardation in PKU patients after birth.
    No preview · Article · Oct 2014 · Human Molecular Genetics

  • No preview · Article · Sep 2014 · Neuropediatrics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.Methods Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ¿M) and NTBC-levels in the therapeutic range (20¿40 ¿M). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).Conclusion Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.
    Full-text · Article · Aug 2014 · Orphanet Journal of Rare Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: As patients with different types of mucopolysaccharidosis (MPS) and mucolipidosis (ML) may present with overlapping clinical features - including coarse face, hepatosplenomegaly, bone dysplasia and claw-hand deformities, collectively also called 'MPS-like phenotype', enzymatic and/or molecular genetic analyses are indispensable for accurate diagnosis and applying specific therapy. In this prospective study, we screened patients with symptoms compatible with MPS for MPS I, II (males) and VI. Methods: Dried blood spots/specimens (DBS) were collected from 200 patients with an MPS-like phenotype and analysed for activities of α-iduronidase (IDUA), iduronate-2-sulphatase (IDS), and arylsulphatase B (ARSB), the enzymes deficient in mucopolysaccharidosis (MPS) type I, II and VI, respectively. For the samples with pathologic enzyme activity, mutational analysis was carried out using the same DBS. Results: Based on enzymatic analysis of 200 DBS samples, a total of 45 (22.5%) showed low activity; 17 for MPS I (8.5%), 11 for MPS II (5.5%) and 9 for MPS VI (4.5%). Enzyme activities were suggestive for ML II/III in 8 (4.0%) cases. For 41 (91.1%) samples, DNA could be extracted from the filter paper. Mutations were identified in 11 (64.7%), 11 (100%), 9 (100%) and 5 (62.5%) patients putatively diagnosed biochemically with MPS I, II, VI, and ML II/III, respectively. Conclusions: DBS enzymatic analysis can be used to diagnose MPS/ML. Initial results should be confirmed by a second enzyme assay and/or by molecular genetic testing. Given the advantages of DBS over other sample types in terms of ease of collection, storage and transportation, DBS are particularly useful for screening patients with an MPS-like phenotype in regions lacking specialised laboratories. In order to ascertain the diagnosis in a large number of cases, patients should be assessed in parallel for at least MPS I, II and VI.
    No preview · Article · May 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteopetrosis is an inherited disorder of impaired bone resorption with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl(-) /H(+) exchanger CLC-7 and the a3 subunit of the vacuolar H(+) -ATPase, respectively. We, and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc/oc mice. The remaining question was, whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n = 1), CLCN7 (n = 3) or TCIRG1 (n = 3). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A- or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis.
    Full-text · Article · Apr 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Combined D,L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182) is a rare neurometabolic disorder clinically characterized by muscular hypotonia, severe neurodevelopmental dysfunction, and intractable seizures associated with respiratory distress. Biochemically, DL-2HGA patients excrete increased amounts of D- and L-2-hydroxyglutarate (D2HG and L2HG, respectively), with predominance of D2HG, and α-ketoglutarate, and show a decrease in urinary citrate. Impaired function of the mitochondrial citrate carrier (CIC) due to pathogenic mutations within the SLC25A1 gene has been identified as the underlying molecular cause of the disease. CIC mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Thus, depletion of cytosolic citrate as well as accumulation of citrate inside mitochondria have been considered to play a role in the pathophysiology of DL-2HGA. Here, we report for the first time on a patient with a genetically confirmed diagnosis of DL-2HGA and treatment with either malate or citrate. During malate treatment, urinary malate concentration increased, but beyond that, neither biochemical nor clinical alterations were observed. In contrast, treatment with citrate led to an increased urinary excretion of TCA cycle intermediates malate and succinate, and by trend to an increased concentration of urinary citrate. Furthermore, excretion of D2HG and L2HG was reduced during citrate treatment. Clinically, the patient showed stabilization with regard to frequency and severity of seizures. Treating DL-2HGA with citrate should be considered in other DL-2HGA patients, and its effects should be studied systematically.
    No preview · Article · Apr 2014 · Journal of Inherited Metabolic Disease
  • [Show abstract] [Hide abstract]
    ABSTRACT: Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life-threatening liver failure, but the benefits of liver transplantation (LTx) are controversial because of frequent severe neurological involvement due to underlying mitochondrial disease. We describe the long-term clinical course of two patients from our institution and give an update on outcomes after LTx in this condition. A further 12 pediatric patients were identified with a systematic search of the literature. All 14 reported patients were transplanted in infancy, despite mild to moderate neurological impairment in some cases. The two DGUOK-deficient patients from our center displayed liver failure and mild to moderate neurological involvement, and have been followed now for five and eight years after LTx respectively. Both patients are alive; they have only mild neurological symptoms. Among the twelve patients identified by the literature review, three have survived long-term (17, 12, and 23 years), eight died during early follow-up, and for one patient no follow-up information was available. The 1-year survival rate was 64%; 36% survived for more than five years. The long-term survivors had a good quality of life. Although survival after LTx for DGUOK deficiency is lower than for other indications, a significant proportion of patients benefit from LTx with long-term survival and a stable neurological situation, in spite of initial neurological abnormalities. Nevertheless, a decision to carry out LTx in patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LTx, despite their absence prior to transplantation. Liver Transpl , 2014. © 2014 AASLD.
    No preview · Article · Apr 2014 · Liver Transplantation

Publication Stats

4k Citations
529.43 Total Impact Points

Institutions

  • 2003-2016
    • University Medical Center Hamburg - Eppendorf
      • • Department of Paediatrics
      • • Department of Paediatric Haematology and Oncology
      Hamburg, Hamburg, Germany
  • 1997-2013
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2004-2011
    • University of Hamburg
      • Department of Paediatrics
      Hamburg, Hamburg, Germany
  • 2004-2009
    • Medical School Hamburg
      Hamburg, Hamburg, Germany
  • 2008
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 1993-2003
    • Christian-Albrechts-Universität zu Kiel
      • • UKSH Klinik für Allgemeine Pädiatrie
      • • UKSH II. Medizinische Klinik und Poliklinik
      Kiel, Schleswig-Holstein, Germany
    • Baylor University
      Waco, Texas, United States
  • 1994
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
  • 1991
    • Children´s Hospital Association
      Overland Park, Kansas, United States
    • The Children's Hospital of Buffalo
      New York City, New York, United States
    • University at Buffalo, The State University of New York
      • Department of Pediatrics
      Buffalo, New York, United States